34
J . Org. Chem. 1983,48, 34-39
A Synthesis of 3@-Hydroxy-5@,14a-bufa-20,22-dienolide from Deoxycorticosterone Philip E. Bauer, Keith S. Kyler, and David S. Watt* Department of Chemistry, University of Wyoming, Laramie, Wyoming 82071
Received June 7, 1982 A new procedure for the synthesis of y-hydroxy-a,&unsaturated thiol esters from ketones employed 1(phenylthio)-l-(trimethylsilyl)-2-propene as an unsaturated homoenolate anion equivalent, and this procedure served as a key step in a synthesis of the a-pyrone ring characteristic of bufadienolides. In particular, the regioand stereoselective trapping of various pregnan-20-ones by the anion of l-(phenylthio)-l-(trimethylsilyl)-2-propene furnished (20S,232)-20-hydroxy-24-(phenylthio)-24-(trimethylsilyl)-23-cholenes and subsequent regioselective oxygenation of the dianions of these adducts provided S-phenyl (20S,22E)-20-hydroxychol-22-ene-24-thioates, Application of this procedure to 3~-hydroxy-21-methoxy-5P,14a-pregnan-20-one furnished S-phenyl (20S,22E)-3~,20-dihydroxy-2l-methoxy-5~-chol-22-ene-24-thioate, which was subsequently cyclized to 38hydroxy-5P,14a-bufa-20,22-dienolide.
The bufadienolidesl isolated from plants and amphibians comprise an intriguing class of steroids that exhibit antineoplastic2and cardiac-stimulant3properties. Prior synthetic work has focused on the elaboration of the apyrone ring characteristic of bufadienolides 1 by a variety of elegant pathway^.^-^ Among these approaches are two recurring problems: either the dehydrogenation of 20bufenolide 24c+6,7a*9 and 20(22)-bufenolide 3s precursors or the cyclization of saturated esters 46 and unsaturated esters 544bd37b proceed in modest yield as shown in Scheme I. To address these problems, we sought to develop a synthetic scheme based on the retroanalysis shown in Scheme 11. (1) (a) Linde, H. H. A,; Meyer, K. Pharmacogn. Phytochem., Int. Congr., 1st 1970, 239. (b) Ode, R. H.; Kamano, Y.; Pettit, G. R. M T P (Med. Tech. Publ. Co.) Int. Reu. Sci.: Org. Chem., Ser. One 1973,8,151. (c) Ode, R. H.; Pettit, G. R.; Kamano, Y. MTP (Med. Tech. Publ. Co.) Int. Reu. Sci.: Org.Chem., Ser. Two 1976,8, 145. (d) Sondheimer, F. Chem. Br. 1965,1, 454. (2) (a) Kupchan, S. M.; Moniot, J. L.; Sigel, C. W.; Hemingway, R. J. J. Org. Chem. 1971, 36, 2611. (b) Kupchan, S. M.; Hemingway, R. J.; Hemingway, J. C. Ibid. 1969,34,3894. (c) Hartwell, J. L.; Abbott, B. J. Ado. Pharmacol. Chemother. 1969, 7, 117. (3) (a) Chem, K. K.; Kovarikova, A. J. Pharm. Sci. 1967,56,1535. (b) Murase, H. Jpn. J.Pharmacol. 1965, 15, 72. (c) Foester, W. Acta Biol. Med. Ger. 1962, 9, 341 (Chem. Abstr. 1963,58, 11846). (d) Tamm, C. 'Proceedings of the First International Pharmacological Meeting"; Wilbrandt, W., Lindgren, P., Ed.; Pergamon Press: London, 1963; Vol. 3, pp 11-26. (4) Synthesis of scillarenin from 15a-hydroxyprogesterone:(a) Radscheit, K.; Stache, U.; Haede, W.; Fritach, W.; Ruschig, H. Tetrahedron Lett. 1969, 3029. (b) Stache, U.; Radscheit, K.; Fritsch, W.; Kohl, H.; Haede, W.; Ruschig, H. Ibid. 1969, 3033. (c) Haede, W.; Fritsch, W.; Radscheit, K.; Stache, U.; Ruschig, H. J u t u s Liebigs Ann. Chem. 1970, 741,92. (d) Stache, U.; Radscheit, K.; Fritach, W.; Haede, W.; Kohl, H.; Ruschig, H. Ibid. 1971, 750, 149. (e) Kohl, H.; Fritach, W.; Haede, W.; Radscheit, K.; Stache, U. S. African Patent 6902400,1969 (Chem. Abstr. 1970, 72, 11729a). (5) Synthesis of bufalin and resibufogenin from 14a-hydroxycortexolone: (a) Sondheimer, F.; McCrae, W.; Salmond, W. G. J. Am. Chem. SOC.1969,91, 1228. (b) Sondheimer, F.; Wife, R. L. Tetrahedron Lett. 1973, 765. (6) Synthesis of b u f a l i and resibufogenin: (a) Pettit, G. R.; Houghton, L. E.; Knight, J. C.; Bruschweiler, F. J. Chem. SOC.,Chem. Commun. 1970,93. (b) Pettit, G. R.; Houghton, L. E.; Knight, J. C.; Bruschweiler, F. J. Org. Chem. 1970, 35, 2895. (7) A synthesis of 3/3-acetoxy-5a,l4a-bufa-20,22-dienolide from 30acetoxy-5a-androstan-17-one:(a) Engel, C. R.; Bouchard, R.; de Krassny, A. F.; Ruest, L.; Lessard, J. Steroids 1969, 14, 637. (b) Engel, C. R.; Dionne, G. Can. J . Chem. 1978,56,424. (8) Synthesis of bufalin and resibufogenin from 3p-hydroxy-5@pregn-14-en-20-one acetate: Yoshii, E.; Oribe, T.; Koizumi, T.; Hayashi, I.; Tumura, K. Chem. Pharm. Bull. 1977,25, 2249. (9) Synthesis of 5/3,14a-bufa-20,22-dienolide from cholic acid: Sarel, S.; Shalon, Y.; Yanuka, Y. J . Chem. SOC.,Chem. Commun. 1970, 80, 81. The quantitative yield reported for the 2,3-dichloro-5,6-dicyanoquinone-mediated dehydrogenation of the enol lactone to the a-pyrone has been questioned: see ref 8.
Scheme I
l
2
-
3
1
o
y
c
~
c
o
2
R
3
4
5
Scheme I il RQ
This approach demanded the development of an unsaturated homoenolate anion equivalentlo 6 that (1) would append a three-carbon unit to a pregnan-20-one at the appropriate level of oxidation for closure to an a-pyrone, (2) would accommodate hydroxyl groups and double bonds elsewhere in the steroid without requiring protection, and (3) would furnish an intermediate 7 that would cyclize to an a-pyrone in acceptable yield. We herein report our (10) For recent references, see (a) Corey, E. J.; Noyori, R. Tetrahedron Lett. 1970, 311. (b) Corey, E. J.; Erickson, B. W.; Noyori, R. J. A m . Chem. Soc. 1971,93,1724. (c) Leroux, Y.; Mantione, R. J. Organomet. Chem. 1971, 30, 295. (d) Carlson, R. G.; Mardis, W. S. J . Org. Chem. 1975,40, 817. (e) Cohen, T.; Bennett, D. A.; Mura, A. J., Jr. Ibid. 1976, 41,2506. (0 Schmidt, R. R.; Talbiersky, J. Angew. Chem., Int. Ed. Engl. 1976, 15, 171. (9) Reich, H. J.; Shah, S. K. J . Am. Chem. SOC. 1977, 99, 263. (h) Wada, M.; Nakamura, H.; Taguchi, T.; Takei, H. Chem. Lett. 1977, 345. (i) Martin, S. F.; Garrison, P. J. Tetrahedron Lett. 1977, 3875. Debal, A.; Cuvigny, T.; Larchgveque, M. Ibid. 1977, 3187.
0022-3263/83/1948-0034$01.50/00 1983 American Chemical Society
J. Org. Chem., Vol. 48, No. 1, 1983
Synthesis of 3~-Hydroxy-5~,14a-bufa-20,22-dienolide
35
Scheme I11 OR
O
d
A
& H
8,R=H 9, R = CH,
l l a , R = H ; R' = OH l l b , R = OH; R = H
10
S I I C H ~ ) ~e
&
,
SAr
$
do
d
HO Ho
ri
17, Ar = C,H, 1 8 , Ar = 0-CH,OC,H,
H
H
19, Ar = C,H, 20, Ar = 0-CH,OC,H,
21
a, CH,I, Ag,O; b, H,, Pd-C, PY; C, kCl6, P(OCH,),, 90%aq i-C,H,OH; d , sec-C,H,Li, 12; e , sec-C,H,Li followed by 0,; f , HBr, CH,CN. Scheme IV
initial efforts to achieve these goals. 1 sec-C.lngLI
Discussion
2 R
A suitable pregnan-20-one to test this approach was prepared from deoxycorticosterone (8) in three steps" as shown in Scheme 111. Conversion of the C-21 hydroxyl group in 8 to a methyl ether and stereoselective reduction of 21-methoxypregn-4-ene-3,20-dione12 (9) using palladium on carbon in pyridine13 furnished 21-methoxy-58-pregnane-3,20-dione (10). The 13C NMR spectrum of 10 displayed c-5and c-19 at 44.9 and 22.6 ppm, respectively, and confirmed the 5/3-stereochemical a~signment.'~ Further stereo- and regioselective reduction15Jeof the C-3 carbonyl group in 10 employed Henbest's iridium chloride-trimethyl phosphite procedure16to obtain the 3P- and 3a-alcohols llb and lla in a 91:9 ratio. The chromatographic separation of 1 la and 11b proved difficult although the benzoate derivative of each isomer was readily separated and fully characterized. Evidence for the 36 stereochemistry in the major isomer llb was again obtained from the 13C NMR spectrum that displayed C-1, C-3, and C-5 at 30.3,67.3, and 36.9 ppm, re~pective1y.l~ Typically, however, the mixture of diastereomers 1 la and 1 lb were not separated but carried forward to the next stage in the synthesis where chromatography gave pure 3P-hydroxylcontaining material. We then developed 1- (phenylthio) 1-(trimethylsilyl)-2propene" (12)as the appropriate unsaturated homoenolate
-
(11) This regioselective route should be contrasted with a much longer route involving C-20 carbonyl protection: Bach, G.; Capitaine, J.; Engel, C. R. Can. J. Chem. 1968, 46, 733. (12) Cole, W. G.;Williams, D. H. J . Chem. SOC.C 1968, 1849. (13) Tsuji, N.; Suzuki, J.; Shiota, M.; Takahashi, I.; Nishimua, S. J. Org. Chem. 1980,45, 2729. (14) Blunt, J. W.; Stothers, J. B. Org. Magn. Reson. 1977, 9, 439. (15) (a) Hadda, Y.M. Y.; Henbest, H. B.; Husbands, Mrs. J.; Mitchell, T. R. B. R o c . Chem. SOC.1964,361. (b) Browne, P. A.; Kirk, D. N. J. Chem. SOC.C 1969,1653. (c) Henbest, H.B.; Mitchell, T. R. B. Ibid. 1970, 785. (d) Pettit, G. R.; Dias, J. R. J. Org. Chem. 1971, 36, 3207. (e) Valcavi, U.;Innocenti, S. Farmaco, Ed. Sci. 1974, 29, 194. (16) For an alternate rhodium-catalyzedhydrogenation, see Nishimura, S.Strem. Chem. 1978, 6 , 7 .
HO
R
SPh I
A*
I
SIlCH3)3
14
12
15
16
anion equivalent 6. As shown in Scheme IV, the anion of this reagent 12 condensed with various ketones 13 to provide the adducts 14. Application of this condensation reaction to various simple ketones as well as selected pregnan-20-ones gave the desired adducts 14 displayed in Table I. Subsequently, the dianions 15 derived from the adducts 14 were exposed to oxygen to afford the y-hydroxy-a,P-unsaturated thiol esters 16. As shown in Table I, this oxidative desilylation procedure converted a variety of adducts 14 to unsaturated thiol esters 16 in modest yield. Although the mechanism is unclear, we suspect that a radical-anion process is involved in which electrostatic considerations dictate the selective trapping of oxygen at (2-24 rather than at (2-22. The yields clearly varied with structure in a fairly unpredictable fashion, and the other major component in most oxidation reactions was unreacted starting material. The oxidation procedure was, as expected, compatible with hydroxyl groups, isolated double bonds and 1,3-dioxane protecting groups but not with tetrahydropyranyl ethers or 1,3-dio~olanes.~* As shown in Scheme 111, application of this sequence to the bufadienolide precursor, 3P-hydroxy-21-methoxy-5Ppregnan-20-one (1lb) initially furnished the adduct 17 in (17) Kyler, K. S.;Watt, D. S. J . Org. Chem. 1981, 46, 5182. (18) (a) Heathcock, C. H.; Ellis, J. E.; Badger, R. A. J . Heterocycl. Chem. 1969,6,139. (b) Mallory, R.A.; Rovinski, S.; Kohen, F.; Scheer, I. J . Org. Chem. 1967, 32, 1417 and references therein.
36 J . Org. Chem., Vol. 48, No. 1, 1983
Bauer et al.
Table I. Addition of l-(Phenylthio)-l-(trimethylsilyl)-2-propene ( 1 2 ) to Ketones 1 3 and Oxidative Desilylation of Adducts 1 4
ketone 1 3
adduct 1 4
c , R = OTHP; R' = R" = H d , R = OCH,; R' = R" = H e , R = R' = O(CH,),O; R" = OCH,
f ,R
=
R'
=
O(CH,),O; R" = OCH,
isolated yield o f 14, %
unsaturated thiol ester 1 6
isolated yield of 16. %
57 a 69
74 51
60
30
b
34
The adduct 14f was prepared by an acid-catalyzed exchange with use of 1 4 e and 1,3a J. Org. Chem. 1 9 8 1 , 4 6 , 5182. The tetrahydropyranyl ether group in 1 4 c was lost during the oxidation t o give 1 6 c where R = OH, R' = H. propandiol.
48% yield. The recovery of unreacted starting material llb raised the yield of 17 to 72%, and the recycling of this material routinely gave good overall yields of the adduct 17. The oxygenation step, however, involved one additional complicating factor in that we needed to generate a trianion from the adduct 17. Problems associated with balancing the insolubility of this trianion species or its ion aggregates at -78 "C against the instability of the allyllithium portion of the trianion at somewhat higher temperatures than -78 OC caused considerable difficulty. Ultimately, the metalation of 17 using sec-butyllithium in a 10% hexamethylphosphoramide-tetrahydrofuransolution containing 12-crown-4at -78 "C and subsequent exposure of the trianion to oxygen gave a 39% yield of the thiol ester 19 in Scheme 111. Again, recovered starting material raised the yield of 19 to 59%. Variation of the solvent, temperature, oxidizing agents such as oxodiperoxymolybdenum hexamethylphosphoramide pyridineIg and other additives such as N,N,N',N'-tetramethylethylenediamine proved futile. Similarly, variation of substrate structure such as the 2-(methoxypheny1)thio analogue 18 afforded no improvement in the yield of the oxidation step. The final step in the synthesis of 3P-hydroxy-5P,14abufa-20,22-dienolide (21)involved the cyclizationz0of the thiol ester 19. Exposure of 19 to hydrobromic acid in refluxing acetonitrile converts 19 to 21 in 51% yield. Although the exact sequence of steps in this conversion is uncertain, the overall process involves the hydrolysis of the thiol ester group, dehydration of the C-20 hydroxyl,21
(19) Minoun, H.; Seree de Roch, L.; Sajus, L. Bull. SOC.Chim. Fr. 1969, 1481. (20) For examples of acid-catalyzed cyclizations leading to &lactones (including a-pyrones), see (a) Wiley, R. H.; Hart,A. J. J. Am. Chem. SOC. 1954, 76,1942. (b) Kochetkov, N. K.; Kudryashov, L. J.; Gottich, B. P. Tetrahedron 1961,12,63. (c) Korte, F.;Scharf, D. Chem. Ber. 1962,95, 443. (d) Fujita, T.; Watanabe, S.; Suga, K.; Kuramochi, T.; Tsukagoshi, F. J. Chem. Tech. BiotechnoL 1979, 29, 31.
isomerization of the C-22 double bond, lactonization, and loss of methanol to give the a-pyrone. The interruption of this reaction after a short time interval allowed the isolation of the carboxylic acid derived from 19 but none of the aldehyde 5. The improved yield in the cyclization of 19 relative to the reported yield^"^^^,'^ for the cyclization of 5 suggests an alternate pathway possibly involving the acetal 22 as an intermediatesz2 The 13C NMR data for n
m
y 22
(21) Prior efforts to prepare the intermediate dienol ether i cri30
cozc H 3
i by a Wittig reaction of methyl 20-oxo-21-norchol-22-en-24-oate with the ylide from (methoxymethy1)triphenylphosphonium chloride was unsuccessful: Pettit, G. R.; Green, B.; Dunn, G. L.; Sunder-Plassmann, P. J . Org. Chem. 1970,35, 1385. (22) A 20(22)-saturated analogue of the hypothetical acetal intermediate in the cyclization was prepared by the mercuric chloride catalyzed methanolysis of the dithioacetal ii: ref 6b.
/--" ii
J. Org. Chem., Vol. 48, No. 1, 1983 37
Synthesis of 3~-Hydroxy-5(3,14a-bufa-20,22-dienolide Table 11. Selected 'jC NMR Dataaib carbon
c-1
c-2 c-3 c-4 c-5 C-6 c-7 C-8 c-9 c-10
c-11 c-12 C-13 C-14 C-15 C-16 (2-17 (2-18 c-19 (2-20 (2-21 c-22 (2-23 C-24 OCH, COC,H, Si(CH313 CH,OC,H, aromatic C-1 aromatic C-2 aromatic C-3 aromatic C-4 aromatic C-5 aromatic C-6
1lb lla (benzoate) (benzoate)
10
llb
37.1 a 37.0 a 212.8 42.3 44.9 25.7 26.5 35.5 40.7 34.9 21.4 38.9 44.1 56.7 24.5 22.9 59.2 13.6 22.6 208.0 78.7
30.3 28.3 67.3 33.9 36.9 26.7 27.0 a 35.6 40.1 36.1 21.5 39.6 45.4 59.4 24.3 23.2 57.5 14.1 25.0 208.7 79.1
30.8 25.2 71.2 31.1 37.6 26.2' 26.5 a 35.8 40.0 35.0 24 .O 39.1 45.0 59.0 24.6 22.9 57.0 13.7 21.2 208.3 78.7
31.9 24.5 70.6 33.2 35.9 a 26.3 28.2 35.5 a 40.4 32.9 20.8 38.9 44.9 58.9 54.2 22.8 56.9 11.4 13.7 208.2 78.7
58.8
59.7
59.2 165.9
59.2 165.9
a, b, c, assignments may be reversed.
132.7 129.5 130.2 128.3
132.7 129.5 131.2 128.3
17
18
29.9 27.8 67.1 33.5 36.5 26.1 26.6 35.1 39.9 35.0 20.9 39.7 42.9 56.8 28.9 23.6 55.4 13.7 22.3 76.6 76.9 34.8 135.7 148.3 59.0
29.9 27.8 67.1 33.5 36.5 26.1 26.6 35.1 39.9 35.0 20.9 39.7 42.9 56.7 23.9 23.6 55.5 13.6 22.3 76.6 76.5 39.5 134.8 149.0 59.0
-1.0
-1.1 55.8 128.2 156.3 125.8 110.3 120.7 125.9
137.7 128.1 128.5 125.1
The central CDCl, signal was set at
compounds in this study appear in Table 11. I n summary, we have developed 1-(phenylthio)-1-(trimethylsilyl)-2-propene (12) as an unsaturated homoenolate anion equivalent that generates a y-hydroxy-a,@-unsaturated carbonyl compound at an oxidation level different than t h e oxidation level of other homoenolate anion equivalentsz3 The reagent was applied t o an expeditious, six-step synthesis of 3/3-hydroxy-Fi@,i+~-bufa-20,22-dienolide that contrasts favorably with other somewhat longer syntheses of t h e a-pyrone ring in bufadienolides. W e are presently investigating other reagents both to improve t h e efficiency of this process and t o accommodate a C-14 double bond necessary for t h e synthesis of naturally occurring bufadienolides. (23) Other unsaturated homoenolate anion equivalents such as Corey's 1,3-bi~(methylthio)propene~~~ could, in principle, be used to prepare the unsaturated thiol ester as shown below. In 'order to compare this method with the oxidative desilylation method, we prepared the unsaturated aldehyde iv in 50% overall yield, which is comparable to the overall yield of thiol ester 19 in the oxidative desilylation procedure. Some difficulty was experienced in purifying the diastereomers iii and in oxidizing iv aihere C-20/C-21 bond cleavage occurred.
6
19 29.9 27.8 67.1 33.5 36.5 26.2 26.6 35.1 39.8 35.1 20.9 40.1 43.5 56.5 23.9 23.9 55.7 14.5 22.8 77.7 77.9 148.4 129.3 188.0 59.4
134.5 127.7 129.1 126.2
20 30.0 27.9 67.1 33.6 36.6 26.2 26.6 35.1 40.2 35.1 20.9 39.8 43.5 56.5 23.9 23.9 56.0 14.4 22.8 77.7 78.0 147.9 131.5 187.4 59.4
21 30.8 25.0 70.6 30.6 37.4 26.2 26.4 35.0 37.9 36.0 20.7 40.1 44.2 51.2 23.8 24.2 55.8 12.9 25.3 118.5 148.6 145.4 115.4 162.2
55.8 136.8 159.4 126.3 111.6 115.9 121.1
77.00.
Experimental S e c t i o n Infrared spectra were determined on a Beckman Microlab 600 spectrometer. The abbreviation TF denotes thin film. NMR spectra were determined on a JEOL 270-MHz SC spectrometer. Mass spectra were determined on either a Varian MAT CH5 or a Du Pont CEC 21-10B mass spectrometer. Melting points were determined with a Thomas-Hoover melting point apparatus and are uncorrected. Elemental analyses were performed by Atlantic Microlabs, Atlanta, GA. GA. General Condensation Procedure for the Preparation of Adducts 14. (3@,205,23Z)-2O-Hydroxy-3-methoxy-24-(phenylthio)-24-(trimethylsilyl)chola-5,23-diene (14d). The procedure of Kyler and Watt" was repeated with 330 mg (1.0 "01) of pregnenolone methyl etherz5(13d) and 287 mg (1.3 mmol) of l-(phenylthio)-l-(trimethylsilyl)-2-propene(12) except that the anion of 12 was added to a solution of 13d in anhydrous THF at 0 "C rather than at -78 "C to afford, after preparative-layer chromatography on Merck silica gel F254 in 1:3:5 ether-hexane-dichloromethane, 325 mg (59%) of 14d: mp 116-117 "C; IR (KBr) 3476, 1578 cm-'; NMR (CDC1,) 6 0.12 (s, 9, Si(CH3),),0.93 (9, 3, (2-18 angular CH,), 1.07 (9, 3, C-19 angular CH,), 1.39 (s, 3, C-21 CH,), 3.43 (s, 3, OCH3), 5.44 (m, 1, C-6 vinyl H), 6.78 (t, 1, J = 5 Hz, C-23 vinyl H), 7.1-7.5 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 534 (M' - HzO, 2), 331 ( 7 ) ,313 (4), 299 (S), 222 (100). Repetition of this experiment on a 10-mmol scale gave a 69% yield of 14d. Anal. Calcd for C34H5202SSi:C, 73.85; H, 9.48. Found: C, 73.92; H, 9.57. Data for Adducts 14: 14a-c are described e1~ewhere.l~ 1 k mp 118-119.5 "C; IR (KBr) 3480,1583cm-l; NMR (CDCl,) 6 0.03 ( 8 , 9, Si(CH3),), 0.84 (9, 3, C-18 angular CH,), 1.02 (s, 3, C-19 angular CH,), 3.37 (9, 3, OCH,), 3.32, 3.43 (AB q, J = 8.8 (24) Rodig, 0. R.; Brown, P.; Zaffaroni, P. J. Org. Chem. 1961, 26, 2431. (25) Hurd, C. D.; Greengard, H. J. Am. Chem. SOC. 1930, 52, 3356.
38 J. Org. Chem., Vol. 48, No. 1, 1983 Hz, 2, CH20CH3),3.95 (m, 4, OCH2CH20),5.37 (m, 1, C-6 vinylic H), 6.65 (t, 1,C-23 vinylic H), 7.08-7.48 (m, 5, aromatic H); mass spectrum (70 eV), mle (relative intensity) 610 (M+,0.2), 592 (5), 565 (4), 389 (loo), 222 (20), 99 (20); exact mass spectrum calcd for C,H,04SSi 610.3512, found 610.3506. 14E mp 154.5-156 "C; I R (KBr) 3460,1583c d ;NMR (CDCl,) 6 0.04 (9, 9, Si(CH,),), 0.84 (9, 3, C-18 angular CHJ, 1.02 (s, 3, C-19 angular CH,), 3.38 (9, 3, OCH,), 3.32, 3.44 (AB q, J = 9.2 Hz, 2, CH20CH3),3.77-4.16 (m, 4, OCH2CH2CH20),5.37 (m, 1, C-6 vinylic H), 6.65 (t, 1,C-23 vinylic H), 7.08-7.48 (m, 5, aromatic H); mass spectrum (70 eV), mle (relative intensity) 624 (M', 0.5), 606 (0.5),579 (l),403 (77),222 (52),113 (100);exact mass spectrum calcd for C3,HS04SSi 624.3668, found 624.3665. Anal. Calcd for C3,HS04SSi: C, 71.10; H, 9.15. Found: C, 71.40; H, 9.18. General Oxidative Desilylation Procedure. S-Phenyl (3j3,20S,22E)-20-Hydroxy-3-methoxyc hola-5,22-diene-24thioate (16d). To 138 mg (0.25 mmol) of 14d in 1.5 mL of anhydrous THF at -78 "C under a nitrogen atmosphere was added 0.56 mL of 1.08 M sec-butyllithium in cyclohexane followed by 0.15 mL of anhydrous hexamethylphosphoramide. The orange solution was stirred at -78 "C for 3 h and exposed to a slow oxygen stream for 30 min. The reaction was quenched with 1.0 mL of water, diluted with ether, washed with water, and dried over anhydrous magnesium sulfate. The crude product was chromatographed on two 20 X 20 cm Merck silica gel F254 preparative-layer plates in 1:3:5 ether-hexane-dichloromethane to afford 62.5 mg (51%) of 16d: mp 146147 "C; IR (KBr) 3500,1663,1624 cm-'; NMR (CDCl,) 6 0.82 (9, 3, C-18 angular CH,), 0.99 (9, 3, C-19 angular CH,), 1.39 (3, s, C-21 CH,), 3.35 (9, 3, OCH,), 6.38 (m, 1, C-6 vinyl H), 6.39 (d, 1,J = 15 Hz, C-23 vinyl H), 7.06 (d, 1, J = 15 Hz, C-22 vinyl H), 7.33-7.62 (m, 5, aromatic H); mass spectrum (70 eV), mle (relative intensity) 494 (M', O.l), 385 (75), 353 (loo), 255 (44), 159 (64), 145 (61), 125 (56), 119 (38); exact mass spectrum calcd for C31H4203S495.2855, found 494.2886. Anal. Calcd for C31H4203S:C, 75.27; H, 8.56. Found: C, 75.30; H, 8.58. Data for 6-Hydroxy-a,@-unsaturatedThiol Esters 16. 16a: mp 124-126 "C; IR (TF) 3473, 1682, 1671, 1625 cm-'; NMR (CDC13) 6 2.59 (s, 1, OH), 6.47 (d, 1, J = 15 Hz, CH=CHCO), 6.9-7.5 (m, 16, aromatic H, CH=CHCO); mass spectrum (70 eV), m l e 237 (M' - SPh). Anal. Calcd for CZ2Hl80&3: C, 76.28; H, 5.24. Found: C, 76.21; H, 5.24. 16b: mp 108-109 "C; IR (KBr) 3448, 1675,1625 cm-'; NMR (CHC1,) 6 1.20-1.80 (m, 22, CH2),6.41, 7.04 (2 d, J = 15.2 Hz, 2, C-22 and C-23 vinylic H), 7.36-7.56 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 346 (8), 328 (6), 237 (100); exact mass spectrum calcd for C,lH3002S346.1965, found 346.1938. Anal. Calcd for CZlH,0&3: C, 72.78; H, 8.73. Found: C, 72.57; H, 8.81. 16c: mp 157.5-159.5 "C (recrystallized from ether-hexane); IR (KBr) 3480, 1670, 1625 cm-'; NMR (CDCl,) 6 0.80, 0.97 (2 s, 6, (2-18 and C-19 angular CH,), 1.35 (9, 3, C-21 CHJ, 3.35-3.6 (m, 1, C-3a H), 5.28 (m, 1, C-6 vinylic H), 6.31, 6.99 (2 d, J = 16 Hz, 2, C-22 and (2-23 vinylic H), 7.33 (s, 5, aromatic H); mass spectrum (70 eV), mle (relative intensity) 371 (85, M+ - SPh), 353 (83), 181 (82), 131 (100). Anal. Calcd for C30H4003S~H,0: C, 72.26; H, 8.49. Found: C, 72.71; H, 8.49. An elemental analysis was also obtained on the 3P-tetrahydropyranyl ether derivative of 16c. Anal. Calcd for CSHMO4S: C, 74.43; H, 8.57. Found: C, 74.22; H, 8.61. 16e: mp 151.5-153.5 "C (recrystallizedfrom hexane); IR (KBr) 3443, 1684 cm-'; NMR (CHCl,) 6 0.80 (s, 3, C-18 angular CH,), 1.02 (s, 3, C-19 angular CH,), 3.38 (5, 3, OCH,), 3.29, 3.47 (AB q , J = 9.2 Hz, 2, CH,OCH&, 3.95 (m, 4, OCH2CH20),5.35 (m, 1,C-6 vinylic H), 6.47, 7.04 (2 d, J = 15.2 Hz, 2, C- 23 and C-24 vinylic H), 7.32-7.72 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 552 (M+,52), 443 (lOO), 399 (13), 345 (13); exact mass spectrum calcd for C3,H4,06S: 552.2909, found 552.2922. 16f isolated as a foam that could not be induced to crystallize; IR (TF) 3442,1683 cm-'; NMR (CHC1,) 6 0.80 (s,3, C-18 angular
Bauer et al. CH3),1.02 (9, 3, C-19 angular CH,), 3.38 (s, 3, OCH,), 3.30, 3.48 (AB q, J = 8.6 Hz, 2, CH,OCH,), 3.76-4.16 (m, 4, OCH2CH2CH20),5.37 (m, 1,C-6 vinylic H), 6.47, 7.04 (2 d, J = 15.8 Hz, 2, C-22 and C-23 vinylic H), 7.35-7.64 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 566 (M+,O.l), 457 (O.l), 402 (O.l), 149 (20), 133 (ll),119 (25), 113 (54); exact mass spectrum calcd for C34H4605S566.3065, found 566.3015. 21-Methoxy-5j3-pregnane-3,20-dione (10). The procedure of Nishimura', was repeated, using 2.23 g of recrystallized 21methoxyprogesterone12 (6) and 290 mg of 10% palladium on carbon in 25 mL of anhydrous pyridine under 30 psi of hydrogen in a Parr shaker for 140 min (final pressure = 21 psi) to afford 1.86 g (83%) of 10: mp 136-138 "C (recrystallized from acetone-hexane); IR (KBr) 1717, 1703 cm-'; NMR (CDCl,) 6 0.67 (9, 3, '2-18 angular CHJ, 1.03 (9, 3, C-19 angular CH,), 3.41 (s, 3, OCH,), 4.01 (AB q, J = 17.1 Hz, 2, CH20CH3);mass spectrum (70 eV), mle (relative intensity) 346 (M+,4), 301 (loo), 273 (18), 255 (56),203 (12),107 (14);exact mass spectrum calcd for CnH,O, 346.2490, found 346.2499. Anal. Calcd for C22H3403: C, 76.26; H, 9.89. Found: C, 76.27; H, 9.91. 3&Hydroxy-21-methoxy-5j3-pregnan-20-one(1lb). The procedure of Browne and Kirk16bwas repeated, using 1.28 g (3.7 mmol) of 10,2.5 mL of distilled trimethyl phosphite and 122 mg of dihydrogen hexachloroiridate(1V)hexahydrate (Alfa) in 32 mL of 90% aqueous isopropyl alcohol under reflux for 93 h to afford, after MPLC chromatography on silica gel with 1:2 dichloromethane-ethyl acetate, 1.13 g (88%) of 9059.5 ratio of 3ahydroxy-21-methoxy-5P-pregnan-20-one (1la) and 3P-hydroxy21-methoxy-5P-pregnan-20-one (llb). The predominant alcohol l l b had the following: IR (KBr) 3340,1699 cm-'; NMR (CDCl,) 6 0.63 (s,3, C-18 angular CH,), 0.96 (s,3, C-19 angular CHJ, 3.41 (s, 3, OCH,), 4.04 (AB q, J = 17.1 Hz, 2, CH20CH3),4.12 (m, 1, C-3a H); mass spectrum (70 eV), mle (relative intensity) 348 (M+, 11, 303 (241, 285 (3), 257 (20), 142 (lo), 100 (100); exact mass spectrum calcd for C22H3603 348.2664, found 348.2639. Anal. Calcd for C,,H,O,: C, 75.81; H, 10.41. Found: C, 75.75; H, 10.40. Complete separation of the epimeric alcohols was best effected by conversion to their benzoates (2.0 equiv of benzoyl chloride/anhydrous pyridine) and MPLC chromatography on silica gel with use of 1:3:5 ether-hexane-dichloromethane to afford an 8% yield of a noncrystallizable foam, 3a-hydroxy-21-methoxy5P-pregnan-20-one benzoate: IR (TF) 1716 (br) cm-'; NMR (CDCl,) 6 0.65 (s, 3, C-18 angular CH,), 0.84 (s, 3, C-19 angular CHJ, 3.41 (s, 3, OCH,), 4.01 (AB q, J = 17.1 Hz, 2, CH,OCH,), 5.29 (m, 1,CHOBz), 7.4-8.2 (m, 5, aromatic H); mass spectrum (70 eV), m / e (relative intensity) 452 (M', l),407 (loo), 257 (71), 105 (34);exact mass spectrum calcd for CBH,O, 452.2987, found 452.2957. Anal. Calcd for CBHM04:C, 76.95; H, 8.91. Found: C, 77.00; H, 8.93. Chromatography also afforded a 76% yield of a more polar benzoate: material, 3P-hydroxy-21-methoxy-5P-pregnan-20-one mp 143-144 "C (recrystallized from dichloromethane-hexane); IR (KBr) 1710 (br) cm-'; NMR (CDCl,) 6 0.65 (s,3, C-18 angular CH,), 1.02 (s, 3, C-19 angular CH3),3.42 (s, 3, OCH,), 4.01 (AB q, J = 17.1 Hz, 2, CH,OCH,), 5.37 (m, 1, CHOBz), 7.4-8.2 (m, 5 , aromatic H); mass spectrum (70 eV), m l e (relative intensity) 452 (M', 0.4), 407 (loo), 257 (97), 105 (67). Anal. Calcd for CBH4004:C, 76.95; H, 8.91. Found: C, 76.93; H, 8.93. (3~,205,232)-3,20-Dihydroxy-21-methoxy-24-(phenylthio)-24-(trimethylsilyl)-5~-chol-23-ene (17). To 577 mg (2.6 mmol, 1.3 equiv) of 12 in 4 mL of anhydrous THF under a nitrogen atmosphere was added 2.4 mL (2.6 mmol) of 1.08 M sec-butyllithium in cyclohexane followed by 0.2 mL of anhydrous HMPA. The solution was stirred for 4 h at -78 "C. To 348 mg (1mmol) of 11 in 2 mL of anhydrous THF at 0 "C was added the anion solution dropwise via a syringe packed in dry ice. An immediate gelatinous precipitate was produced that was allowed to stand for 3 h at 0 "C. The reaction was quenched with water, diluted with ether, washed with water, and dried over anhydrous magnesium sulfate. The product was chromatographed on three 20 X 20 cm Merck silica gel F254 plates in 1:3:5 ether-hexane-dichloromethane to afford 275 mg (48%) of 17 isolated as a foam
Synthesis of 3P-Hydroxy-5P,14a-bufa-20,22-dienolide that could not be induced to crystalline: IR (KBr) 3450,1580 cm-'; NMR (CHC13)6 0.12 (s,9, Si(CH,),), 0.89 (s,3, C-18 angular CH3), 1.04 (9, 3, C-19 angular CH3),3.45 (9, 3, OCH3),4.20 (m, 1, C-3a H), 6.71 (t, 1, C-23 vinylic H), 7.1-7.5 (m, 5, aromatic H); mass spectrum (70 eV), m/e (relative intensity) 552 (M' - H20,0.5), 525 (2), 415 (l),331 (34), 257 (34), 222 (100);exact mass spectrum calcd for C,HNO3SSi.H20 552.3457, found 552.3486. The recovery of 115 mg of 11 raised the yield of 17 to 72%. Anal. Calcd for C34H,,03SSi: C, 71.52; H, 9.53. Found: C, 71.35; H, 9.56. 1-[(2-Methoxyphenyl)thio]-l-(trimethylsilyl)-2-propene. The procedure of Hurd and Greengard26was repeated using 10 g (71.4 mmol) of 2-methoxybenzenethiol, 8.64 g (71.4 mmol) of allyl bromide, and 1.64 g (71.4 mmol) of sodium in 50 mL of absolute ethanol to afford 10.3 g (80%) of 2-methoxyphenyl allyl sulfide: bp 79-83 "C (0.3 mm). The procedure of Kyler and Watt" was repeated with 5.0 g (27.8 mmol) of this sulfide, 25.5 mL (33.4 mmol, 1.2 equiv) of 1.31 M sec-butyllithium in cyclohexane, and 7.25 g (66.7 mmol, 2.4 equiv) of chlorotrimethylsilane to afford 3.61 g (51%) of l-(2-methoxyphenyl)-1-(trimethylsilyl)-2-propene: bp 97-100.5 "C (0.15 mm): IR (TF)2953,1623,1577 cm-'; NMR (CDC13) 6 0.19 (9, 9, Si(CH3),), 3.28 (d, J = 9.3 Hz, 1,CHCH= CH2),3.89 (9, 3, OCH3),4.87-5.10 (m, 2, CHCH=CH2), 5.64-5.82 (m, 1,CHCH=CH2),6.76-7.29 (m, 4, aromatic H); mass spectrum (70 eV), m/e (relative intensity) 252 (M', 14), 167 (141, 165 (14), 73 (100). Anal. Calcd for C13HmOSStC, 61.85; H, 7.99. Found C, 61.75; H, 8.03. (3~,20S,23Z)-3,20-Dihydroxy-21-methoxy-24-[ (2-methoxyphenyl)thio]-24-(trimethylsilyl)-5~-chol-23-ene (18). The procedure described for the preparation of 17 was repeated with 200 mg (0.575 mmol) of l l b and 337 mg (1.49 mmol, 1.3 equiv) of l-[(2-methoxyphenyl)thio]-l-(trimethylsilyl)-2-propene to afford, after chromatography on Merck silica gel F254 in 1:2 dichloromethane-ethyl acetate, 128 mg (37%) of 18: mp 62-65 "C; IR (TF) 3441, 2924, 1577 cm-'; NMR (CDCl,) 6 0.06 (9, 9, Si(CH3)3),0.81 ( ~ , 3c-18 , angular CH3), 0.96 ( ~ , 3c-19 , angular CH3), 2.48-2.79 (m, 2, C-22 CH2),3.36 (9, 3, CH20CH3),3.24-3.45 (m, 2, CH20CH3),3.90 (s, 3, aromatic OCH,), 6.62-7.13 (m, 4, aromatic H); mass spectrum (70 eV), m/e (relative intensity) 349 (M' CloH190SSifrom C-20,22 bond cleavage, 20), 252 (loo), 73 (42). The recovery of 101 mg of l l b raised the yield of 18 to 75%. Anal. Calcd for C3,Ha04SSi: C, 69.95; H, 9.39. Found: C, 69.78; H, 9.43. S-Phenyl (3@,20S,22E)-3,20-Dihydroxy-2 1-methoxy-58chol-22-ene-24-thioate (19). To 81.5 mg (0.143 mmol) of 18 and 50.4 mg (0.286 mmol,2 equiv) of 12-crown-4in 3 mL of anhydrous THF under a nitrogen atmosphere at -78 "C was added 0.48 mL (0.515 mmol,1.2 equiv) of 1.08 M sec-butyllithium in cyclohexane. To this heterogeneous mixture was added 0.3 mL of anhydrous HMPA, and the mixture was stirred for 5 h at -78 "C. Oxygen gas was bubbled into the solution for 30 min, and the reaction was quenched with 1mL of water. The product was diluted with ether, washed with water, and dried over anhydrous magnesium sulfate. The crude product was chromatographed on a 20 X 20 cm Merck silica gel F254 plate in 1:lO ethyl acetate-dichloromethane to afford 29 mg (39%) of 19 as a foam that could not be induced to crystallize: IR (KBr) 3428,1683,1625 cm-'; NMR (CDC13)6 0.76 (9, 3, (2-18 angular CH3),0.95 (9, 3, C-19 angular CH3),3.37 (8, 3, OCH3),3.29, 3.47 (AB q , J = 9.2 Hz, 2, CH20CH3), 4.10 (m, 1, C-3a H), 6.46 (d, J = 15.1 Hz, 1, C-23 H), 7.02 (d, J = 15.1 Hz, 1,C-22 H), 7.4-7.6 (m, 5, aromatic H); mass spectrum (26) Gsell, L.;Tamm, C.Helu. Chim. Acta 1969, 52, 551.
J. Org. Chem., Vol. 48, No. 1, 1983
39
(70 eV), m/e (relative intensity) 403 (M+ - SPh, 20), 385 (86), 257 (44), 155 (100). The recovery of 27 mg of 18 raised the yield of 19 to 59%. Anal. Calcd for C3,H,06SCH30H: C, 70.56; H, 8.88. Found: C, 70.72; H, 8.76. S-(2-Methoxyphenyl) (3,9,2OS,22E)-3,20-Dihydroxy-21methoxy-5j3-chol-22-ene-24-thioate (20). The procedure described for the preparation of 19 was repeated with 32.3 mg (0.054 mmol) of 18 to afford 8.8 mg (30%) of 20: IR (TF) 3558, 2928, 1675, 1628, 1582 cm-'; NMR (CDCl,) 6 0.77 (s, 3, C-18 angular CH3),0.96 (s,3, C-19 angular CH3), 3.36 (s,3, CHZOCH,), 3.26-3.49 (m, 2, CH20CH3),3.85 (s, 3, aromatic OCH3), 4.09 (m, 1, C-3a H), 6.47 (d, J = 16 Hz, 1,C-23 vinylic H), 6.95-7.44 (m, 5, aromatic and C-22 vinylic H); mass spectrum (70 eV), m/e (relative intensity) 468 (6), 394 (19), 236 (25), 159 (44), 144 (100). Anal. Calcd for C32H4502S: C, 70.81; H, 8.54. Found: C, 70.57; H, 8.62. 3~-Hydroxy-5~,14a-bufa-20,22-dienolide (21). To 10.0 mg (0.0195 mmol) of 19 in 1mL of acetonitrile was added 34 pL of 48% hydrobromic acid. The solution was refluxed for 2.5 h; an additional 34 pL of 48% hydrobromic acid was added; and the solution was refluxed an additional 9 h at which time TLC indicated that the starting material 19 was consumed. The product was diluted with ether, washed successivelywith aqueous sodium bicarbonate solution, water, and brine, and dried over anhydrous magnesium sulfate. The product was chromatographed on a 20 X 20 cm Merck silica gel F254 plate in 1:l ethyl acetate-hexane to afford 3.8 mg (51%) of 21 as a gum that could not be induced to crystallize: IR (TF) 3413, 2923, 1718 cm-'; NMR (CDCl,) 6 0.53 (9, 3, C-18 angular CH,), 0.97 (s, 3, C-19 angular CH3),6.28 (d, J = 9.2 Hz, 1, C-23 vinylic H). The C-21 and C-22 protons appear as a multiplet at 6 7.2-7.3 that is partially obscured by the CHC1, signal. NMR (Me2SO-d3)6 0.47 (9, 3, C-18 angular CH3), 0.90 (s, 3, C-19 angular CH3), 3.88 (br s, 1, C-3a H), 6.28 (d, J = 9.9 Hz, 1, C-23 vinylic HI,7.51 (dd, J22,23 = 9.3 Hz, J21,22 = 2.6 Hz, C-22 vinylic H), 7.62 (br s, 1, C-21 vinylic H); mass spectrum (70 eV), m/e (relative intensity) 370 (M', l),352 (4), 298 (2), 215 (18),107 (50); exact mass spectrum calcd for CaHa03 370.2509, found 370.2510.
Acknowledgment. We thank the National Institutes of Health (Grant CA 30065) and t h e Wyoming Heart Association for their generous financial support. We also thank the University of Wyoming's Central Committee for a Basic Research Grant, the National Science Foundation (Grant CHE-8026553) for funds to purchase a JEOL 270-MHz NMR spectrometer, and G. D. Searle for a generous supply of certain steroids. Finally, we t h a n k Professor G. R. P e t t i t and Dr. Keith A. M. Walker for various authentic samples and Dr. Richard A. Heppner of t h e Laramie Energy Technology Center for determining mass spectra. Registry No. 8, 64-85-7; 9, 20380-14-7; 10, 83862-48-0;lla, 83862-49-1;lla benzoate, 83862-50-4;l l b , 83862-51-5;l l b benzoate, 83862-52-6;12,78905-13-2;13d, 511-26-2;14a, 83862-53-7; 14b, 83862-54-8; 1 4 ~79409-72-6; , 14d, 83862-55-9;14e, 83876-13-5; 14f, 83862-56-0;16a, 83862-57-1; 16b, 83862-58-2; 16c, 83862-59-3; 16c,THP, 83862-60-6; 16d, 83862-61-7; 16e, 83862-62-8; 16f, 83862-63-9; 17, 83862-64-0; 18, 83876-14-6; 19, 83862-65-1;20, 83897-12-5;21,83862-66-2; 2-methoxybenzenethiol,7217-59-6;d y l bromide, 106-95-6; 2-methoxyphenyl allyl sulfide, 38477-80-4; chlorotrimethylsilane, 75-77-4; 1-(2-methoxyphenyl)-l-(trimethylsilyl)-2-propene, 83862-67-3.
